Neurokinins

The group of peptides known as tachykinins include substance P, substance K or neurokinin A, and neuromedin K, ie, neurokinin B, as well as a number of nonmammalian peptides. All members of this family contain the conserved carboxy-terrninal sequence Phe-X-Gly-Leu-Met-NH2, where X is an aromatic, ie, Phe or Tyr, or branched aliphatic, eg, Val or lie, amino acid. In general, this C-terminal sequence is cmcial for tachykinin activity (33) in fact, both the methionineamide and the C-terminal amide are cmcial for activity. The nature of the X residue in this sequence determines pharmacological identity (34,35) thus the substance P group contains an aromatic residue in this position, while the substance K group contains an aliphatic residue (33). 

Neurokinin effects are terrninated by proteolysis. In vitro acetylcholinesterase (ACE) and enkephalinase can hydrolyze substance P. However, there appears to be no clear evidence that either acetylcholinesterase or ACE limit the actions of released substance P. Enkephalinase inhibitors, eg, thiorphan, can augment substance P release or action in some systems but the distribution of enkephalinase in the brain does not precisely mirror that of substance P. There appears to be a substance P-selective enzyme in brain and spinal cord. 

Capsaicin, an active ingredient in red pepper, is well known for its ability to release and deplete substance P in sensory C fibers. However, this action is not specific for substance P, as neurokinin A, calcitonin gene-related peptide (CGRP), and somatostatin also are released. 

C-fibre afferents from the aitways contain peptide tachykinin transmitters such as substance P (SP) and neurokinins A and B (NKA and NKB). Stimulation of these nerves can also cause local release of these mediators at their peripheral terminal, allowing them to enhance the activity of the RARs. SP, NKA and NKB act at the tachykinin receptors (NK4-NK3), and so understandably, antagonists for NK2 in particular appear promising in cough. 

The neurokinin, substance P (SP), may be involved as a sensory transmitter in afferent vagal nerves involved in the vomiting reflex. Both SP and its receptors (NKi receptors) have been detected in several areas of the brain associated with vomiting, including the AP, NTS and dorsal motor vagal nucleus. The neurokinin can activate neurons in the AP and NTS. SP is present also in sensory nerves in the gut as well as being co-localised with serotonin in some enterochromaffin cells. 

The neuropeptides are peptides acting as neurotransmitters. Some form families such as the tachykinin family with substance P, neurokinin A and neurokinin B, which consist of 11 or 12 amino acids and possess the common carboxy-terminal sequence Phe-X-Gly-Leu-Met-CONH2. Substance P is a transmitter of primary afferent nociceptive neurones. The opioid peptide family is characterized by the C-terminal sequence Tyr-Gly-Gly-Phe-X. Its numerous members are transmitters in many brain neurones. Neuropeptide Y (NPY), with 36 amino acids, is a transmitter (with noradrenaline and ATP) of postganglionic sympathetic neurones. 

Substance P is a member of a group of polypeptides known as neurokinins or tachykinins. It is thought to be the primary neurotransmitter for the transfer of sensory information from the periphery to the spinal cord and brain. Substance P as well as neurokinin NKX receptors has been detected in vagal afferent neurons in the area postrema, nucleus tractus solitarius and dorsal motor nucleus of the vagus. Substance P has been shown to increase the firing rate of neurons in the area postrema and nucleus tractus solitarius and to produce retching when applied directly to these areas in animal studies. 

Tachykinin NH receptor TK N r Neurokinin-1 receptor, substance P receptor... 

Tachykinin NK2 receptor TK NK2r Neurokinin-2 receptor, neurokinin A receptor, substance K receptor, neurokinin-alpha receptor, Neuromedin L receptor... 

Tachykinin NK3 receptor TK NK3r Neurokinin-3 receptor, neurokinin B receptor, neurokinin-beta receptor, Neuromedin K receptor... 

The common C-terminal amino acid sequence required for exerting activity at tachykinin receptors is shown in bold endokinin C and D lack the C-terminal Met and are almost devoid of affinity at these receptors. In red, the sequence of neurokinin A of which neuropeptide-gamma and neuropeptide-kappa are elongated forms and neurokinin A (3-10) is a product of beta or gamma-TAC1 mRNAs or an NKA metabolite active at tachykinin receptors. In blue, the sequence of human HK-1 of which endokinin A and B are elongated forms. 

Neurokinin-1 Receptor. A homology model of the neurokinin-1 (NKi) receptor was built from the X-ray structure of rhodopsin, using the MOBILE (modeling binding sites including ligand information explicitly) approach. In this procedure, a preliminary model is generated, which is afterwards refined... 

Evers A, Klebe G. Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model. J Med Ghent 2004 47 5381-92. 

Some propeptides lead to the production of different, in terms of receptor affinities, peptides (substance P and neurokinin A act on neurokinin 1 and 2 receptors, respectively). 

Different peptides from the same gene product (met and leu enkephalin, substance P and neurokinin A). The former two act on the same receptor, the delta opioid receptor, whereas the latter act on different receptors, the neurokinin 1 and 2 receptors. Despite this, the receptors for the neurokinins produce the same direction of effect, a slow depolarisation, even though their distribution differs. 

These are a family of peptides which include substance P, isolated in 1931 but only sequenced in 1971. This peptide has been extensively studied since it was the first major peptide to be extracted from brain but only now are useful antagonists becoming available. Two closely related peptides were then isolated from mammalian tissues and can be added to a number of other tachykinins, many of which are found in amphibians. The name tachykinins originated from the vasoactive effects of substance P but the nomenclature has been resolved into calling the three major mammalian peptides substance P, neurokinin A (NKA) and neurokinin B (NKB) with the corresponding receptors being numbered 1 to 3. The order of potencies at the three receptors as follows ... 

Neurokinin receptors NK2 receptor agonists (e.g. GR64349) have an anxiogenic profile in animal models while the antagonists (GR100679) have an anti-anxiety effect. However, NKi receptor antagonists have also been reported to have antianxiety activity in the social interaction test (File 1997). 

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